Nanotherapeutic Delivery of Resveratrol Analogs as a Pre-Treatment of Allografts in Solid Organ Transplantation

白藜芦醇类似物的纳米治疗递送作为实体器官移植中同种异体移植物的预处理

基本信息

批准号：
9306943
负责人：
ANN-MARIE BROOME
金额：
$ 7.48万
依托单位：
MEDICAL UNIVERSITY OF SOUTH CAROLINA
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-07-01 至 2018-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9306943
关键词：
Acute Adaptive Immune System Address Adverse effects Allografting Amino Acid Sequence Anti-Inflammatory Agents Anti-inflammatory Antigen Presentation Antioxidants Binding Biological Biological Availability Biological Preservation Cardiac Cardiac Myocytes Cell Line Cell surface Chronic Clinical Cryopreservation Devices Drug Delivery Systems Drug Targeting Encapsulated Endothelial Cells Endothelium Engineering Future Glare High Pressure Liquid Chromatography Hour Human Image Imaging Techniques Immune system Immunofluorescence Immunologic Immunosuppression Immunosuppressive Agents Immunotherapeutic agent In Vitro Inbred BALB C Mice Inflammation Inflammatory Integrin alphaVbeta3 Literature Longevity Mainstreaming Measures Mediation Mediator of activation protein Methods Micelles Modality Mus Organ Donor Organ Harvestings Organ Transplantation Oxidative Stress Pathology Pathway interactions Perfusion Pharmaceutical Preparations Phenotype Phosphotransferases Play RGD (sequence)Research Personnel Resolution Resveratrol Role Sampling Solid Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization Staining method Stains Surface System Therapeutic Thrombosis Time Tissues Toxic effect Translational Research Transplantation Umbilical vein Universities Wisconsin analog cytokine dosage end-stage organ failure fluorophore immunoregulation improved in vivo nanoparticle nanotherapeutic novel organ transplant rejection polyphenol prevent public health relevance receptor mediated endocytosis targeted delivery therapeutic target trafficking uptake

项目摘要

DESCRIPTION (provided by applicant): Organ transplantation has become the modality for the treatment of end-stage organ failure. Chronic rejection remains a leading cause of graft loss in the long term. One of the primary reasons for this is that the adaptive immune system plays an integral role and is just emerging as a critical mediator in organ transplantation. Accumulating evidence indicates that the adaptive immune system is activated at the time of organ transplantation and remains in play longer than initially recognized by the release of inflammatory triggers, including oxidative stress. Various translational research efforts have identified pathways and potential therapeutics that may allay the effects of chronic rejection by conferring an enhanced inflammation resolution and a tolerogenic phenotype in allograft recipients. Polyphenols, such as resveratrol (RSV), reduce a range of pathologies associated with organ transplantation, including inflammation. The activities of these compounds are achieved via various mechanisms including their well-characterized antioxidant effects and immunosuppression effects. The clinical use of RSV is not; however, mainstream as issues regarding poor selectivity, dosage, toxicity and delivery methods are unresolved. Here, we propose a novel delivery method wherein an immunotherapeutic is encapsulated in a biologically inert nanoparticle and delivered in a targeted manner to an allograft in vivo. To this end, we have generated RSV analogs to improve bioavailability and toxicity of RSV. The encapsulation of RSV analogs in micelle nanoparticles and its impact on harvested organs requires proof-of-concept studies. We will engineer a micelle nanoparticle which is conjugated to the amino acid sequence of Arg-Gly-Asp (cRGD), which serves as a targeting moiety directed towards the αvβ3 integrin on endothelial cells which optimizes cellular uptake. Near infrared fluorophores are also conjugated to the surface, allowing for analysis of micelle uptake and cellular localization within the endothelium of donor organ allografts. We hypothesize that targeted local delivery of packaged RSV via cold storage perfusion will increase concentrations of RSV intracellular and preserve aortic allograft cytoarchitecture.

描述（由申请人提供）：器官移植已成为治疗终末期器官衰竭的方式，从长远来看，慢性排斥仍然是移植物丧失的主要原因之一是适应性免疫系统。越来越多的证据表明，适应性免疫系统在器官移植时被激活，并且持续发挥作用的时间比最初认为的炎症触发因素释放的时间要长。各种转化研究工作已经确定了一些途径和潜在的治疗方法，可以通过增强同种异体移植受者的炎症消退和耐受表型来减轻慢性排斥反应的影响，例如白藜芦醇（RSV），减少一系列相关的病理。这些化合物的活性是通过多种机制实现的，包括其明确的抗氧化作用和免疫抑制作用，但 RSV 的临床应用并不是主流。关于选择性差、剂量、毒性和递送方法的问题尚未解决。在此，我们提出了一种新的递送方法，将免疫治疗药物封装在生物惰性纳米颗粒中，并以靶向方式递送至体内同种异体移植物。最后，我们生成了 RSV 类似物，以提高 RSV 的生物利用度和毒性。将 RSV 类似物封装在胶束纳米颗粒中及其对收获器官的影响需要进行概念验证研究，我们将设计一种与氨基酸缀合的胶束纳米颗粒。 Arg-Gly-Asp (cRGD) 序列，作为针对内皮细胞上的 αvβ3 整合素的靶向部分，优化细胞近红外荧光团也与表面结合，从而可以分析供体器官同种异体移植物内皮内的胶束摄取和细胞定位，我们发现通过冷藏灌注定向局部递送包装的 RSV 将增加细胞内 RSV 的浓度并保存。主动脉同种异体移植细胞结构。